rs2099104

chr16-89553132-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_003119.4(SPG7):c.1933T>A(p.Ser645Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000812 in 1,606,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.22

Genes affected

SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_003119.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022359908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.1933T>A	p.Ser645Thr	missense_variant	14/17	ENST00000645818.2
SPG7	NM_001363850.1	c.1933T>A	p.Ser645Thr	missense_variant	14/18
SPG7	XM_047434537.1	c.1060T>A	p.Ser354Thr	missense_variant	9/13
SPG7	XM_047434540.1	c.619T>A	p.Ser207Thr	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.1933T>A	p.Ser645Thr	missense_variant	14/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000818 AC: 191 AN: 233420 Hom.: 0 AF XY: 0.000687 AC XY: 87 AN XY: 126710

Gnomad AFR exome AF: 0.000208

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000984

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.000820 AC: 1193 AN: 1454600 Hom.: 0 Cov.: 31 AF XY: 0.000799 AC XY: 578 AN XY: 723048

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000209

Gnomad4 NFE exome AF: 0.000960

Gnomad4 OTH exome AF: 0.000516

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74484

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000837 Hom.: 0

Bravo AF: 0.000835

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000693 AC: 84

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 01, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2021	Identified as heterozygous without a second variant in SPG7 in several individuals with hereditary spastic paraplegia; in one family, the authors did not consider the variant disease causing as it was absent in at least one affected family member (Elleuch et al., 2006; Arnoldi et al., 2008; Morais et al., 2017).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22571692, 27535533, 28832565, 18200586, 16534102) -

Hereditary spastic paraplegia 7 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	13
Dann	Benign	0.11
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.56	T
Polyphen		0.0030	.;.;B;.;.;.;.;.;.
MVP		0.51
MPC		0.19
ClinPred		0.018	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Varity_R		0.093
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2099104; hg19: chr16-89619540;